Why is there motor deterioration in Parkinson’s disease during systemic infections-a hypothetical view

Brugger, Florian; Erro, Roberto; Balint, Bettina; Kägi, Georg; Barone, Paolo; Bhatia, Kailash P.

doi:10.1038/npjparkd.2015.14

Cited by 61 publications

(64 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Prolonged exposure to low levels of TLR4 agonists leads to switching to a pro-inflammatory response, which increases with time and so cannot be reversed without intervention. Furthermore, it is recognized that patients with PD suffering from intercurrent infective/inflammatory illnesses undergo deterioration in their PD, and a variety of reasons have been suggested to underlie this [ 3 ]. Our data would support the hypothesis that systemic inflammatory cytokines may accelerate the cytokine-induced neuronal damage that drives PD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

et al. 2018

View full text Add to dashboard Cite

Despite the wealth of genomic and transcriptomic data in Parkinson's disease (PD), the initial molecular events are unknown. Using LD score regression analysis, we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiological concentrations of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory response with time, including TNF-α production. ROS and cell death in primary neuronal cultures were significantly reduced by TLR4 antagonists revealing that an indirect inflammatory mechanism involving cytokines produced by glial cells makes a major contribution to neuronal death. Prolonged exposure to low levels of alpha-synuclein oligomers sensitizes TLR4 responsiveness in astrocytes and microglial, explaining how they become pro-inflammatory, and may be an early causative event in PD.

show abstract

Section: Discussionmentioning

confidence: 99%

Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In this sense, the activation of microglial cells has been extensively reported in both retinal and brain diseases 3 , 79 . On the other hand, it has been previously shown that systemic conditions can worsen and exacerbate the symptoms of chronic neurodegeneration in degenerative diseases as Parkinson’s and Alzheimer’s disease, accelerating the progression of the disease 40 , 80 – 83 . Therefore, our results suggest a possible harmful effect of systemic inflammation on the progression of retinal degenerative diseases that could be extrapolated to brain neurodegenerative disorders, such as Parkinson’s or Alzheimer’s diseases.…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy

et al. 2018

View full text Add to dashboard Cite

Retinal neurodegenerative diseases involve a scenario of inflammation and cell death that leads to morphological alterations and visual impairment. Non-ocular inflammatory processes could affect neurodegenerative retinal disorders and their progression, at least in part by activating microglial cells and releasing pro-inflammatory cytokines. Our purpose was to study the consequences of a systemic inflammatory process in the progression of retinal degeneration in P23H rats, a retinitis pigmentosa (RP) model. In order to induce a mild chronic systemic inflammation, we administered low doses of lipopolysaccharide (LPS) from age P20 to P60 to dystrophic P23H rats and healthy SD rats. Visual responsiveness was assessed by electroretinography (ERG). The morphological state of the retinas was analyzed by fluorescent immunohistochemistry (IHC), evaluating the number, morphology, and connectivity of different neuronal populations by means of cell type-specific markers. Microglia density, distribution, and degree of activation were evaluated by IHC and flow cytometry. The expression levels of inflammation- and apoptosis-related genes were analyzed by qRT-PCR arrays. Low-dose LPS administration did not induce significant functional or morphological changes in the retina of SD rats, although at the molecular level, we detected expression changes in genes related to apoptosis. Otherwise, systemic injection of LPS into P23H rats induced a further deterioration in the ERG response, with greater loss of photoreceptors and worsening of synaptic connectivity, accompanied by increasing numbers of microglial cells, which also showed a more intense activation state. Several inflammation- and apoptosis-related genes were upregulated. Our results indicate that chronic exacerbation of the inflammatory response in response to LPS accelerates neurodegeneration in dystrophic P23H rats, suggesting that in patients with ocular neurodegenerative diseases, peripheral damage, as a systemic infection or chronic inflammatory process, could accelerate disease progression, and should be taken into account in order to select an appropriate therapy to revert, block or slow-down the degenerative process.

show abstract

“…Peripheral infections may enhance neurodegeneration either via direct toxicity of bacterial or viral toxins, or by circulating cytokines. PD patients with viral or bacterial infections exhibit deterioration of both motor and cognitive function, suggesting that inflammation caused by infections may be deleterious and a contributor to disease (Brugger et al, 2015). Interestingly, the highly pathogenic H5N1 avian flu virus is capable of entering the CNS and induces neuroinflammation via microglia activation and increases α-synuclein aggregation in mice (Jang et al, 2009).…”

Section: Lrrk2 Is Associated With Infection and Inflammationmentioning

confidence: 99%

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s

2020

View full text Add to dashboard Cite

It is becoming increasingly accepted that there is an interplay between the peripheral immune response and neuroinflammation in the pathophysiology of Parkinson's disease (PD). Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene are associated with familial and sporadic cases of PD but are also found in immune-related disorders, such as inflammatory bowel disease (IBD) and leprosy. Furthermore, LRRK2 has been associated with bacterial infections such as Mycobacterium tuberculosis and Salmonella typhimurium. Recent evidence suggests a role of LRRK2 in the regulation of the immune system and modulation of inflammatory responses, at a systemic level, with LRRK2 functionally implicated in both the immune system of the central nervous system (CNS) and the periphery. It has therefore been suggested that peripheral immune signaling may play an important role in the regulation of neurodegeneration in LRRK2 as well as non-LRRK2-associated PD. This review will discuss the current evidence for this hypothesis and will provide compelling rationale for placing LRRK2 at the interface between peripheral immune responses and neuroinflammation.

show abstract

Why is there motor deterioration in Parkinson’s disease during systemic infections-a hypothetical view

Cited by 61 publications

References 44 publications

Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s

Contact Info

Product

Resources

About